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Cancer Technologies

Engineering Tools to Understand and Halt Collective Cancer Invasion

Friday, October 25, 2024
8:30 AM – 8:45 AM EST
Location: Room 336

Introduction:  Invasive and rotational collective cell migration behaviors are essential for normal epithelial tissue development and maintenance. Neoplastic epithelial cells can aberrantly activate invasive collective migration (ICM), resulting in duct-like structures with or without expression of cell-cell adherens junctions, and this behavior is thought to drive metastatic dissemination. Rotational collective migration (RCM), a developmental program used to form glandular structures, has not previously been observed in neoplastic epithelial cells. This has been attributed to their loss of adherens junctions. Yet, microglandular adenomas and acinar cell carcinomas of the breast, salivary gland, and pancreas are characterized by a spherical morphology containing a central lumen and exhibit indolent clinical behavior. This suggests that neoplastic cells can undergo RCM, and it may be favorable. We previously observed that within populations of both normal mammary epithelial cells and triple-negative breast cancer (TNBC) cells, some cells form acinus-like structures while others form duct-like structures when seeded in confining, high-density type I collagen. Here we show that RCM and ICM give rise to these structures, and we leverage this heterogeneity to determine what initiates RCM versus ICM in cancerous cells.

Materials and

Methods:  First, we developed a Cellular Potts computational model to ask how cell polarization, cell-cell adhesion, and matrix remodeling can each contribute to the emergence of RCM and ICM in confining extracellular matrix (ECM) conditions. To model cell dynamics, the CPM relies on minimization of the overall energy of the system using the Hamiltonian. We built on its earliest application, simulating cell sorting by assuming differential adhesion between different cell types, by incorporating additional terms for cell motility, cell-ECM interactions and proliferation. To test model predictions, we developed an integrated biophysical imaging platform to measure cytoskeletal dynamics, cell traction, and matrix degradation simultaneously for individual cells. Knockdown (KD) and inhibitor experiments were used to gain mechanistic insights. Mouse model experiments validated the identified mechanisms in the context of mammary gland development.

Results, Conclusions, and Discussions: Our findings suggests that local matrix remodeling driven by MMPs gives rise to long protrusions and cell polarization that results in ICM, whereas global matrix remodeling mediated by both MMPs and adhesion-based physical cleavage limits protrusion length and lifetime and results in RCM. Inhibition of MMP-mediated matrix cleavage in vitro and in vivo does not abrogate collective migration, but instead biases cells towards RCM. RCM and ICM behaviors are conserved for both normal and neoplastic epithelial cells when embedded in a confining ECM, regardless of whether they express cadherin-based cell-cell junctions. These findings shift a paradigm, which held that the initiation of RCM behaviors requires adherens junctions. Ongoing work will determine the mechanisms by which MMP activity is spatially regulated to give rise to ICM versus RCM, which may lead to new strategies to prevent or halt ICM behaviors that are thought to be responsible for metastatic spread.

Acknowledgements (Optional):